Creation and validation of the acute heart failure risk score: AHFRS.

Our aims were to create and validate a clinical decision rule to assess severity in acute heart failure. We conducted a prospective cohort study of patients with symptoms of acute heart failure who attended the emergency departments (EDs) of three hospitals between April 2011 and April 2013. The following data were collected on arrival to or during the stay in the ED: baseline severity of symptoms; presence of decompensated comorbidities; number of hospital admissions/visits to EDs for acute heart failure during the previous 24 months; triggers of the exacerbation; clinical signs and symptoms; results of ancillary tests requested in the ED; treatments prescribed; and response to the initial treatment in the ED. The main outcome was poor course during the acute phase, in-hospital for admitted patients and during the first week following the ED visit for discharged patients, this being a composite endpoint that included death, admission to an intensive care unit, need for invasive mechanical ventilation, cardiac arrest and use of non-invasive mechanical ventilation. Multivariate logistic regression models were developed. Predictors of poor course in acute heart failure were oedema on chest radiography, visits to the ED and/or admissions in the previous two years, and levels of glycemia and blood urea nitrogen (areas under the curve of 0.83 in the derivation sample, and 0.82 in the validation sample). Four clinical predictors available in the ED can be used to create a simple score to predict poor course in acute heart failure.Clinical Trials.gov ID: NCT02437058.

Role of Myocardial Collagen in Severe Aortic Stenosis With Preserved Ejection Fraction and Symptoms of Heart Failure.

INTRODUCTION AND OBJECTIVES: We investigated the anatomical localization, biomechanical properties, and molecular phenotype of myocardial collagen tissue in 40 patients with severe aortic stenosis with preserved ejection fraction and symptoms of heart failure. METHODS: Two transmural biopsies were taken from the left ventricular free wall. Mysial and nonmysial regions of the collagen network were analyzed. Myocardial collagen volume fraction (CVF) was measured by picrosirius red staining. Young's elastic modulus (YEM) was measured by atomic force microscopy in decellularized slices to assess stiffness. Collagen types I and III were measured as CIVF and CIIIVF, respectively, by confocal microscopy in areas with YEM evaluation. RESULTS: Compared with controls, patients exhibited increased mysial and nonmysial CVF and nonmysial:mysial CVF ratio (P < .05). In patients, nonmysial CVF (r = 0.330; P = .046) and the nonmysial:mysial CVF ratio (r = 0.419; P = .012) were directly correlated with the ratio of maximal early transmitral flow velocity in diastole to early mitral annulus velocity in diastole. Both the CIVF:CIIIVF ratio and YEM were increased (P ≤ .001) in nonmysial regions compared with mysial regions in patients, with a direct correlation (r = 0.895; P < .001) between them. CONCLUSIONS: These findings suggest that, in patients with severe aortic stenosis with preserved ejection fraction and symptoms of heart failure, diastolic dysfunction is associated with increased nonmysial deposition of collagen, predominantly type I, resulting in increased extracellular matrix stiffness. Therefore, the characteristics of collagen tissue may contribute to diastolic dysfunction in these patients.

Association of cystatin C with heart failure with preserved ejection fraction in elderly hypertensive patients: potential role of altered collagen metabolism.

OBJECTIVES: Cystatin C has been shown to be associated with heart failure with preserved ejection fraction (HFPEF). In addition, myocardial fibrosis has been involved in diastolic dysfunction in HFPEF. Therefore, we hypothesized that increased cystatin C levels may be associated with altered collagen metabolism, contributing to diastolic dysfunction in patients with HFPEF. METHODS: One hundred and forty-one elderly hypertensive patients with HFPEF were included. Cardiac morphology and function was assessed by echocardiography. Circulating levels of cystatin C, biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I) and degradation [matrix metalloproteinase-1 (MMP-1) and its inhibitor TIMP-1] and osteopontin were analyzed by ELISA. Twenty elderly sex-matched patients with no identifiable cardiac disease were used as controls. In-vitro studies were performed in human cardiac fibroblasts. RESULTS: Compared with controls, cystatin C was increased (P < 0.001) in patients with HFPEF, even in those with a normal estimated glomerular filtration rate (eGFR; P < 0.05). Cystatin C was directly correlated with the estimated pulmonary capillary wedge pressure (P < 0.01), TIMP-1 and osteopontin (P < 0.001) and inversely correlated with MMP-1:TIMP-1 (P < 0.01), but not with carboxy-terminal propeptide of procollagen type I or MMP-1 in all patients with HFPEF. These associations were independent of eGFR. In vitro, osteopontin (P < 0.01) and TIMP-1 (P < 0.001) increased in the supernatant of cardiac fibroblasts exposed to cystatin C. CONCLUSION: In patients with HFPEF of hypertensive origin, cystatin C is increased and associated with diastolic dysfunction and alterations in collagen metabolism independently of eGFR. An excess of cystatin C might contribute to diastolic dysfunction in HFPEF by facilitating myocardial fibrosis via accumulation of osteopontin and TIMP-1.

Myocardial Collagen Cross-Linking Is Associated With Heart Failure Hospitalization in Patients With Hypertensive Heart Failure.

BACKGROUND: Excessive myocardial collagen cross-linking (CCL) determines myocardial collagen's resistance to degradation by matrix metalloproteinase (MMP)-1 and interstitial accumulation of collagen fibers with impairment of cardiac function. OBJECTIVES: This study sought to investigate whether CCL and a newly identified biomarker of this alteration are associated with hospitalization for heart failure (HHF) or cardiovascular death in patients with HF and arterial hypertension in whom other comorbidities were excluded. METHODS: Endomyocardial biopsies and blood samples from 38 patients (invasive study), and blood samples from 203 patients (noninvasive study) were analyzed. Mean follow-ups were 7.74 ± 0.58 years and 4.72 ± 0.11 years, respectively. Myocardial CCL was calculated as the ratio between insoluble and soluble collagen. The ratio between the C-terminal telopeptide of collagen type I (CITP) and matrix metalloproteinase-1 (CITP:MMP-1) was determined in blood samples. RESULTS: Invasive study: CCL was increased (p < 0.001) in patients compared with controls. Patients were categorized according to normal or high CCL values. Patients with high CCL exhibited higher risk for subsequent HHF (log-rank test p = 0.022), but not for cardiovascular death. CITP:MMP-1 was inversely associated with CCL (r = -0.460; p = 0.005) in all patients. Receiver operating characteristic curves rendered a CITP:MMP-1 cutoff ≤1.968 (80% sensitivity and 76% specificity) for predicting high CCL. Noninvasive study: Patients were categorized according to CITP:MMP-1 ratio values as normal ratio (>1.968) or low ratio (≤1.968). Patients with a low ratio exhibited higher risk for HHF (log-rank test p = 0.014), which remained significant after adjustment for relevant covariables (adjusted hazard ratio: 2.22; 95% CI: 1.37 to 3.59, p = 0.001). In addition, CITP:MMP-1-based categorization yielded significant integrated discrimination and net reclassification improvements (p = 0.003 and p = 0.009, respectively) for HHF over relevant risk factors. CITP:MMP-1 was not associated with the risk of cardiovascular death. CONCLUSIONS: Excessive myocardial CCL is associated with HHF in hypertensive patients with HF. In this population, the serum CITP:MMP-1 ratio identifies patients with increased CCL and high risk of HHF.

Galectin-3 and histological, molecular and biochemical aspects of myocardial fibrosis in heart failure of hypertensive origin.

AIMS: The aim of this study was to investigate whether galectin-3 (Gal-3) is associated with myocardial histological and molecular parameters related to fibrosis and with the circulating biomarkers of the extracellular generation of mature fibril-forming collagen types I (C-terminal propeptide of procollagen type I, PICP) and III (N-terminal propeptide of procollagen type III, PIIINP) in two independent studies of hypertensive patients with heart failure (HF). METHODS AND RESULTS: Endomyocardial biopsies and blood samples from 39 HF patients (invasive study), and blood samples from 220 HF patients (non-invasive study) were analysed. Necropsies (n = 7) and blood samples (n = 20) from healthy subjects were used as controls. In the invasive study myocardial mRNA and protein expression of Gal-3 and collagen types I and III, plasma Gal-3 and serum PICP and PIIINP were all significantly increased in patients compared with controls. Neither myocardial nor plasma Gal-3 were correlated with myocardial collagen and circulating biomarkers; whereas PICP was correlated with myocardial total (r = 0.819, P < 0.001) and collagen type I (r = 0.744, P < 0.001) deposition, PIIINP was not. In the non-invasive study both plasma Gal-3 and serum PICP were increased (P < 0.001) in patients compared with controls. No correlation was found between Gal-3 and PICP in HF patients. CONCLUSIONS: These findings show that although an excess of cardiac and systemic Gal-3 is present in patients with HF of hypertensive origin, this molecule is not associated with histological, molecular and biochemical parameters related to myocardial fibrosis in these patients.

Factors associated with mortality in patients with exacerbation of chronic obstructive pulmonary disease hospitalized in General Medicine departments.

We aim to improve knowledge on risk factors that relate to mortality in subjects with exacerbation of chronic obstructive pulmonary disease (COPD) who are hospitalized in General Medicine departments. In a cross-sectional multicenter study, by means of a logistic regression analysis, we assessed the possible association of death during hospitalization with the following groups of variables of participating patients: sociodemographic features, treatment received prior to admission and during hospitalization, COPD-related clinical features recorded prior to admission, comorbidity diagnosed prior to admission, clinical data recorded during hospitalization, laboratory results recorded during hospitalization, and electrocardiographic findings recorded during hospitalization. A total of 398 patients was included; 353 (88.7%) were male, and the median age of the patients was 75 years. Of these patients, 21 (5.3%) died during hospitalization. Only 270 (67.8%) received inhaled ß(2) agonists during hospitalization, while 162 (40.7%) received angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. The median of predicted FEV(1) prior to admission was 42%. A total of 350 patients (87.9%) had been diagnosed with two or more comorbid conditions prior to admission. An association was found between increased risk of death during hospitalization and the previous diagnoses of pneumonia, coronary heart disease, and stroke. In conclusion, comorbidity is an important contributor to mortality among patients hospitalized in General Medicine departments because of COPD exacerbation.

Filling pressures and collagen metabolism in hypertensive patients with heart failure and normal ejection fraction.

This study was designed to evaluate the association between circulating biomarkers of collagen metabolism and elevated left-sided filling pressures (FPs), as assessed from elevated estimated pulmonary capillary wedge pressure (ePCWP), in hypertensive patients with heart failure with normal ejection fraction. Echocardiography was performed and ePCWP was calculated from the formula ePCWP=1.90+1.24(maximum early transmitral flow velocity in diastole:tissue Doppler early mitral annulus velocity). The biomarkers of collagen synthesis (carboxy-terminal propeptide of procollagen type I) and degradation (matrix metalloproteinase [MMP] 1 and tissue inhibitor of MMP-1 [TIMP-1]) were analyzed by ELISA methods. Seventy-eight patients with normal FPs (ePCWP < or =15 mm Hg) and 78 with elevated FPs (ePCWP >15 mm Hg) were included. Compared with controls, the levels of the 3 biomarkers were increased in the 2 groups of patients. The MMP-1:TIMP-1 ratio, an index of MMP-1 activity, was increased in patients with normal FPs and unchanged in patients with elevated FPs. Patients with elevated FPs exhibited higher TIMP-1 levels and a lower MMP-1:TIMP-1 ratio than patients with normal FPs. ePCWP was independently associated with TIMP-1 (r=0.349; P<0.001) and the MMP-1:TIMP-1 ratio (r=-0.240; P<0.01) in all of the patients. Receiver operating characteristic curves showed that a cutoff value of TIMP-1 of 1557 ng/mL provided 64% sensitivity and 67% specificity for predicting elevated FPs with a relative risk of 3.71 (95% CI: 1.91 to 7.22). These findings suggest that, in hypertensive patients with heart failure with normal ejection fraction and elevated FPs, collagen synthesis predominates over degradation because of a relative excess of TIMP-1. This imbalance can facilitate myocardial fibrosis, which, in turn, may contribute to the elevation of FPs in these patients.